Known and selected novel arylmethylenyl derivatives of thiazolidinones, imidazolidinones and oxazolidinones useful as antiallergy agents and anti-inflammatory agents

ABSTRACT

The present invention is for selected novel compounds, as well as, pharmaceutical compositions and methods of use for known and the selected novel compounds both of the formula ##STR1## having activity useful for treating allergies and inflammation.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of Ser. No. 375,794, filed Jul. 5,1989, which is a continuation-in-part of Ser. No. 334,346, filed Apr.10, 1989, which is a continuation-in-part of Ser. No. 198,528, filed May25, 1988, all now abandoned.

BACKGROUND OF THE INVENTION

It is now found that Compounds from among known and selected novelarylmethylenyl derivatives of thiazolidinones, oxazolidinones orimidazolidinones have activity useful for treating allergies orinflammation.

Thus, the present invention is for selected novel compounds, as well as,pharmaceutical compositions and methods of use for known compounds andthe selected novel compounds of the formula (I) ##STR2## andpharmaceutically acceptable salts thereof; wherein Ar is (i) phenylunsubstituted, (ii) phenyl substituted by from one to three of loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, NR₁₀ R₁₁ whereinR₁₀ and R₁₁ are independently hydrogen or lower alkyl, NO₂, mercapto, orlower alkylthio, (iii) naphthyl; (iv) benzofuranyl, [v) benzothiophenyl,(vi) 2- or 3-thienyl, (vii) 2- or 3-indolyl, (viii) 2- or 3-furanyl, or(ix) 2-, 3-, or 4-pyridyl;

Y and Y₁ is oxygen or sulfur;

X is sulfur, oxygen, NH or NCH₃ and

X₁ is NH or NC₃ with the proviso that when Ar is substituted phenyl, thesubstituents are either not 3,5-di(isopropyl)-4-hydroxy or if X₁ =NH,X=S, Y=S not 3,5-di(t-butyl) together with 4-hydroxy.

Japanese Application No. 84-133826 as found in Derwent Abstracts No.87-076379/11 discloses new3,5-diisopropylbenzylidene-2,4-imidazolidinone and the analogousthiazoles with antiallergic and tyrosine kinase inhibiting activity aswell as other heterocyclic containing compounds. EP No. 211,670A asdescribed in Derwent 87-051809/08 describes compounds excluded by theproviso above having a 3,5-diisobutylbenzyledene substituent useful fortreating inflammation, ischaemia induced cell damage and arthritis.Thus, known heterocyclic compounds are not as closely related as thesenamed here and are excluded from the present invention.

A French Patent No. 2,169,334, C. H. Boehringer Sohn, Oct. 12, 1973describes a series of N-substituted oxazoles as antiarthritics.antirheumatics, and immunosuppressants having the formula ##STR3## whichare not included in the present invention.

Copending application PD-3518 is for novel compounds having a3,5-di-tertiarybutyl-4-hydroxyphenyl moiety so its disclosure relatingto references in the Background of the Invention is incorporated hereinby reference.

The compounds of the formula I have a hitherto unknown pharmaceuticalactivity useful for treating allergic or inflammatory conditions ordiseases. The invention compounds are now also found to have activity asinhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatmentof conditions advantageously affected by such inhibition includinginflammation, arthritis, pain, pyrrhia, and the like. Thus, the presentinvention is also a pharmaceutical composition for diseases orconditions advantageously affected by activity inhibiting singly ortogether 5-lipoxygenase and cyclooxygenase or method of use therefor.Therefore, the present invention is particularly a pharmaceuticalcomposition for the treatment of allergy or inflammation which comprisesan antiallergy or antiinflammatory effective amount of a compound of theformula I together with a pharmaceutically acceptable carrier. Further,the present invention is a method for treating allergies or inflammationin subject suffering therefrom which comprises administering a compoundof the formula I in unit dosage form.

The present invention is also the novel selected compounds of theformula I noted hereinafter having activity heretofore unknown foranalogous compounds.

Among the known compounds for the compositions or methods of use of thepresent invention the following are referenced for compounds listed forthe Examples of the invention:

    ______________________________________                                        Example No.                                                                             Reference                                                           ______________________________________                                        1         J. Chem. Soc., pp. 958-65 (1946)                                    2         J. Org. Chem., 26, p. 1326 (1961)                                   3         Chem. Ber., pp. 459-69 (1941)                                       4         J. Chem. Soc., pp. 3547-52 (1950)                                   5         J.C.S., p. 1165 (1954)                                              6         J. Org. Chem., p. 1326 (1961)                                       7         U.S. Pat. No. 3,843,797/JACS, p. 2357 (1951)                        8         C.A. 89: 100767m, JACS, p. 2357 (1951)                              9         Tet., p. 2781 (1969)                                                10        Canadian J. Chem., p. 2089 (1959)                                   12        Ger. Pat. DE 3,433,475/C.A. 103, 928404                             17        J.O.C., p. 32 (1956)                                                18        Tet., p. 2781 (1969)                                                19        Tet., p. 2781 (1969)                                                20        Tet., p. 2781 (1969)                                                21        J. Ind. Chem. Soc., p. 77 (1984)                                    22        J. Ind. Chem. Soc., p. 77 (1984)                                    26        See Example 8 above                                                 28        Int. J. Sulf. Chem. Part A, p. 261 (1972)                           29        C.A. 76 (5), 25152h                                                 30        C.A. 79 (25), 143522p                                               32        C.A. 76 (5), 25152h                                                 34        C.A. 79 (25), 143522p                                               36        Biol. Mem. 9, 200 (1984)                                            38        Zh. Or. Khim, p. 212 (1983)                                         40        J.C.S. (1), p. 385 (1984)                                           41        C.A. 89: 100767n                                                    42        Chem. Phar. Bull., p. 1619 (1986)                                   43        Int. J. Sulf. Chem. Part A, p. 261 (1972)                           44        J. Pharm. Soc. Jap., p. 154 (1956)                                  45        Ger. Pat. DE 3,433,475                                              48        J.C.S., p. 3547 (1950)                                              49        C.A. 7, 9543a                                                       50        C.A. 47, 9543a                                                      68        C.A. 71 (17), 81253a                                                69        Zh. Ob. Khm 26, p. 3092 (1956)                                      71        Ukrain Khim Zh. 16, p. 545 (1950)                                   83        Chem. Pharm. Bull., p. 1619 (1986)                                  86        Am. Chem. J., p. 368 (1911)                                         87        JACS, p. 1606 (1913)                                                90        JACS, p. 1606 (1913)                                                91        Monats, p. 352 (1961)                                               92        Chem. Pharm. Bull., p. 1619 (1986)                                  96        Roecz, Chem., p. 1381 (1984)                                        103       U.S. Pat. No. 3,017,270                                             104       Egypt J. Chem., 26, 301 (1983)                                      105       French Pat. No 1,604,530                                            ______________________________________                                    

The selected novel compound of the present invention are found inExamples 11, 13-16, 51-53, 55-63, 64, 70, 72-79, 80, 82, 88, 97, and99-101, 106-111.

Accordingly, the present invention is

(a) a selected novel compound as in the noted examples heretofor or asalt thereof;

(b) a method for preparing a novel selected compound or apharmacologically acceptable salt thereof;

(c) a pharmaceutical composition comprising a compound of formula (I) ora physiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier therefor;

(d) a method for preparing such compositions;

(e) a method for the inhibition of histamine by use of a nontoxic,effective, inhibitory amount of a compound of formula I or aphysiologically acceptable salt thereof;

(f) a method for the prophylaxis or treatment of disease or condition ina mammal, including man, comprising the administration to said mammal ofa nontoxic, therapeutically or prophylactically effective amount of acompound of formula I or a physiologically acceptable salt thereof;

(g) a method for the prophylaxis or treatment of any individualcondition described herein, in a mammal, including man, comprising theadministration to said mammal of a nontoxic therapeutically orprophylactically effective amount of a compound of formula I or aphysiologically acceptable salt thereof;

(h) a method for the prophylaxis or treatment of allergy or inflammatorycondition in a mammal, including man, comprising administration to saidmammal of a nontoxic, effective, antiallergic or antiinflammatory amountof a compound of formula I or a physiologically acceptable salt thereof;

(i) a novel compound as set out in the examples noted heretofor or aphysiologically acceptable salt thereof for use in medicine, especiallyas defined in (f)-(h) above;

(j) use of a compound of formula I or a physiologically acceptable saltthereof in the manufacture of medical therapeutic agents, particularlythose for use as defined in (f)-(h) above; and

(k) any novel feature described herein.

SUMMARY OF THE INVENTION

The present invention is a pharmaceutical composition and method of useas defined above for compounds of the formula I as well as the novelcompounds also as noted above.

A preferred embodiment of the present invention is the composition ormethod of use for a compound of the formula (II) ##STR4## orpharmaceutically acceptable salts thereof; wherein X and Y are asdefined above, R₁, R₂, R₃, R₄ and R₅ are independently H, lower alkyl,lower alkoxy, OH, halogen, CF₃, NR₁₀ R₁₁ wherein R₁₀ and R₁₁ are asdefined above, NO₂, mercapto, or lower alkylthio, wherein of from one tothree of R₁, R₂, R₃, R₄, and R₅ are other than hydrogen, but excludingR₁, R₂, R₃, R₄ and R₅ which are 3,5-di(2-isopropyl) and 4-OH or whichare 3,5-di(t-butyl) and 4-OH when X is NH, or both X and Y are S.

A preferred embodiment of the formula II of the present invention is thecomposition or method of use for a compound of the formula (III)##STR5## or pharmaceutically acceptable salts thereof; wherein R₁, R₂,R₃, R₄ and R₅ are as defined above.

Another preferred embodiment of the formula II of the present inventionis the composition or method of use for a compound of the formula (IV)##STR6## or pharmaceutically acceptable salts thereof; wherein R₁, R₂,R₃, R₄ and R₅ are as defined above.

Also among the preferred embodiment of the formula II is the compositionand method of use for the compound of the formula (V) ##STR7## orpharmaceutically acceptable salts thereof; wherein R₁, R₂, R₃, R₄ and R₅are as defined above.

Another preferred embodiment of the formula II is the composition andmethod of use for the compound of the formula (VI) ##STR8## orpharmaceutically acceptable salts thereof; wherein R₁, R₂, R₃, R₄ and R₅are as defined above.

Another preferred embodiment of the formula II is the composition andmethod of use for the compounds of the formula (VII) ##STR9## orpharmaceutically acceptable salts thereof; wherein X₂ is NH or NCH₃ andR₁, R₂, R₃, R₄ and R₅ is as defined above.

Another preferred embodiment of the formula II is the composition andmethod of use for the compounds of the formula (VIII) ##STR10## orpharmaceutically acceptable salts thereof wherein R₁, R₂, R₃, R₄ and R₅are as defined above. And finally, a preferred embodiment of the formulaII is the composition and methods of use for the compounds of theformula VIIIA ##STR11## or pharmaceutically acceptable salts thereof;wherein R₁, R₂, R₃, R₄ and R₅ are as defined above.

The most preferred embodiment of the formula II is the composition andmethod of use for the following compounds which inhibit the release ofhistamine from human basophils as described hereinafter in the HHB assaystimulated with anti IgE at an IC₅₀ less than 20 μM.

5-[(2,5-dimethoxyphenyl)methylene]-2-thioxo-4-thiazolidinone,

5-[2,4,5-trimethoxyphenyl)methylene]-2-thioxo-4-thiazolidinone,

5-[(3,4,5-trimethoxyphenyl)methylene]-2-thioxo-4-thiazolidinone,

5-[(3,4-dichlorophenyl)methylene]-2-thioxo-4-thiazolidinone,

5-[(3,4-dimethoxyphenyl)methylene]-2-thioxo-4-thiazolidinone,

5-[(3,5-dimethoxy-4-hydroxyphenyl)methylene)-2-thioxo-4-thiazolidinone,

5-[(3,5-dimethyl-4-hydroxyphenyl)methylene)-2-thioxo-4-thiazolidinone,

5-[(5-bromo-4-hydroxy-3-methoxyphenyl)methylene)-2-thioxo-4-thiazolidinone,

5-[(4-methoxyphenyl)methylene)-2-thioxo-4-thiazolidinone,

5-[(5-hydroxy-4-methoxyphenyl)methylene)-2-thioxo-4-thiazolidinone,

5-[(3,5-dimethoxyphenyl)methylene]-2-thioxo-4-thiazolidinedione,

5-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]2,4-thiazolidinedione,

5-[(4-hydroxy-3-methoxyphenyl)methylene]-2,4-thiazolidinedione,

5-[(4-hydroxy-3-methoxyphenyl)methylene]-2-thioxo-4-oxazolidinone,

5-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-2-thioxo-4-oxazolidinone,

2-thioxo-5-[(3,4,5-trimethoxyphenyl)methylene]-4-oxazolidinone,

5-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-2-thioxo-4-imidazolidinone.

Novel compounds which inhibit singly or together 5-lipoxygenase andcyclooxygenase are found by determining percent inhibition in ARBL/ARBCWhole Cell 5-lipoxygenase and Cyclooxygenase Assays andCarrageenan-Induced Rat Foot Paw Edema-2 (CFE-2) Assay describedhereinafter.

Among the preferred compounds as determined in the ARBL/ARBC and CFE-2assays are the following:

2,4-thiazolidione,5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-, (E)-

4-oxazolidinone,5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-

2,4-oxazolidinone,5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-,

2,4-oxazolidinedione, 5-(4-hydroxy-3,5-dimethoxy-phenyl)methylene-, and

4-thiazolidinone, 5-[(4-bromophenyl)methylene]-2-thioxo-.

The most preferred novel compound of the present invention now foundhaving activity which inhibits 5-lipoxygenase and cyclooxygenase are5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2,4-thiazolidinedioneand5-[(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-thioxo-4-oxazolidinone.

Thus, the present invention is also a pharmaceutical composition for thetreatment of conditions advantageously affected by the inhibition of5-lipoxygenase and/or cyclooxygenase which comprises an amount effectivefor the treatment of the condition of a compound of the formula I orvarious preferred embodiments and the pharmaceutically acceptable acidaddition or base salt thereof together with a pharmaceuticallyacceptable carrier. The condition is meant to include, for example,arthritis or other inflammatory diseases, allergic conditions ordiseases, pain, fever, and psoriasis, but now preferably inflammatorydiseases.

The present invention is also a method for treatment of the condition asnoted above in a mammal, including humans, suffering therefrom with acompound of the formula I or the pharmaceutically acceptable acidaddition or base salt thereof, in unit dosage form. The invention alsoprovides for use of any such compound of formula I or particularlyvarious preferred embodiments or salt thereof in the manufacture ofmedical therapeutic agent.

Pharmaceutical composition or use of the compound or salt of formula Iis meant to include treatment understood to be prophylactic pertinent tothe foregoing named condition.

A DETAILED DESCRIPTION OF THE INVENTION

In the present invention "lower alkyl" is alkyl of from one to sixcarbons, inclusive, and means methyl, ethyl, propyl, butyl, pentyl, orhexyl and isomers thereof.

"Lower alkoxy" means methoxy, ethoxy, propoxy, butoxy, pentoxy, orhexoxy and isomers thereof.

"Lower alkylthio" means methylmercapto, ethylmercapto, propylmercapto,butylmercapto, pentylmercapto, or hexylmercapto and isomers thereof.

"Halogen" is chloro, bromo, fluoro, or iodo.

Generally, the selected novel compounds of formula I as well as theknown compounds are prepared by processes that are known or are preparedby processes analogous to those that are known from known startingmaterials or starting materials that can be prepared by known methods.For example, the following starting materials are obtained as follows:

3-Bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde areprepared according to Paal, Chem. Ber. 28 (1895), 2407.

4,5-Dimethoxy-2-hydroxybenzaldehyde is prepared according to Robinson &Head, J. Chem. Soc. (1930), 2440.

3-Methoxy-5-hydroxybenzaldehyde is prepared according to Ben, et al, J.Org. Chem. 50 (1985), 2238.

3,5-Diisopropyl-4-hydroxybenzaldehyde and 3,5-dimethyl4-hydroxybenzaldehyde are prepared according to U.S. Pat. No. 4,009,210.

3-(dimethylamino)methyl-4-hydroxy-5-methoxybenzaldehyde is preparedaccording to Hemetsberger, Monats. Chem. 102 (1971), 1110.

3-Methylhydantoin is prepared according to Guler and Moodie, J. Chem.Soc. Perk II (1980), 1752.

A scheme for preparation of the compounds of formula I above is asfollows: ##STR12## wherein Ar, X₁, X and Y are as defined above.

More particularly, the present invention includes compounds of type 1:##STR13## where R₁, R₂, R₃, R₄ and R₅ are as defined above. Thesecompounds are named as substituted5-phenylmethylene-2-thioxo-4-oxazolidinones, or5-phenylmethylene-2,4-oxazolidinediones.

Certain thiazolidinones and oxazolidinones are acidic (pKa ˜3-6) due tothe presence of a tautomeric proton on the heterocyclic ring: ##STR14##

These compounds can form salts with inorganic and organic bases,including choline derivatives.

If the parent oxazolidinone or thiazolidinone and choline free base or acholine derivative (such as choline bicarbonate or choline chloride) arecombined in a suitable solvent (such as an alcohol, water, or analcohol/water solution), the choline salt can generally be obtained byprecipitation from solution or by evaporation of the reaction solution.

A general method of preparation of these compounds is the aldolcondensation of an aldehyde 2 with an active methylene compound 3(Scheme 1 above). This condensation can be carried out in alcoholicsolvents in the presence of a base such as ammonia, ammonium salts, orpiperidine, or with mineral acid ##STR15## catalysis. A particularlyfavored procedure is the use of anhydrous sodium acetate in glacialacetic acid, with heating at reflux for 1-24 hours. References to thisprocedure include: G. R. Newkome and A. Nayak, in Advances inHeterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Eds.,Academic Press, New York, N.Y., Vol. 25, p. 83 and N. K. Ushenko and T.E. Gorizdra, Ukrain Khim. Zhur., 16, 545 (1950).

An alternate procedure for the preparation of the above compound whenY=O is the preparation of the corresponding oxazole 4 followed byoxidation/hydrolysis to the desired oxazole I wherein X is O, X₂ is NHand Y is O (Scheme 2): ##STR16##

For the preparation of 4, see, for example, F. C. Brown, Chem. Rev., 61,463 (1961), and the (Newkome) reference previously cited. For theconversion 4 to I of Scheme 2, see also J. W. Clark-Lewis, Chem. Rev.,58, 63 (1958), and N. A. Shenberg, L. S. Guseva, A. I. Ginak, and E. G.Sochilin, Zhur. Organ. Khim., 14, 1323 (1978).

Variations of the above Scheme 1 are also readily prepared by themethods of Scheme 1' discussed above. These are shown here in Scheme 1"as follows. ##STR17##

An alternate procedure for the preparation of the above noted oxazole Iwherein X is 0, X₁ is NH, and Y is 0 is by an alkylation/hydrolysisprocedure (Scheme 2') as follows: ##STR18##

The procedure of Scheme 2' is essentially that of N. A. Shenberg, L. S.Guseva, A. I. Ginak, and E. G. Sochilin, Zhur. Organ. Khim., 14, 1323(1978); and J. S. H. Davies, W. Hook, and F. Long, J. Chem. Soc., 30(1950).

The compounds of formula I are useful both in the free acid form, in theform of base salts where possible, and in the form of acid additionsalts. The three forms are within the scope of the invention. Inpractice, use of the salt form amounts to use of the base form.Appropriate pharmaceutically acceptable salts within the scope of theinvention are those derived from mineral acids such as hydrochloric acidand sulfuric acid; and organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving thehydrochloride, sulfamate, methanesulfonate, benzenesulfonate,p-toluenesulfonate, and the like, respectively or those derived frombases such as suitable organic and inorganic bases. Examples of suitableinorganic bases for the formation of salts of compounds of thisinvention include the hydroxides, carbonates, and bicarbonates ofammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc,and the like.

Salts may also be formed with suitable organic bases. Bases suitable forthe formation of pharmaceutically acceptable base addition salts withcompounds of the present invention include organic bases which arenontoxic and strong enough to form such salts. These organic bases forma class whose limits are readily understood by those skilled in the art.Merely for purposes of illustration, the class may be said to includemono-, di-, and trialkylamines, such as methylamine, dimethylamine, andtriethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-,and triethanolamine; amino acids such as arginine, and lysine;guanidine; N-methyglucosamine; N-methylpiperazine; morpholine;ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl)aminomethane; and the like. (See for example, "Pharmaceutical Salts," J.Pharm. Sci., 66(1), 1-19 (1977).)

The acid addition salts of said basic compounds are prepared either bydissolving the free base of compound I in aqueous or aqueous alcoholsolution or other suitable solvents containing the appropriate acid orbase and isolating the salt by evaporating the solution, or be reactingthe free base of compound I with an acid as well as reacting compound Ihaving an acid group thereon with a base such that the reactions are inan organic solvent, in which case the salt separates directly or can beobtained by concentration of the solution.

The base salts of compounds of formula I described above are prepared byreacting the appropriate base with a stoichiometric equivalent of theacid compounds of formula I to obtain pharmacologically acceptable basesalts thereof.

The acid solution salts of said basic compounds are prepared either bydissolving the free base in aqueous or aqueous alcohol solution or othersuitable solvents containing the appropriate acid and isolating the saltby evaporating the solution, or by reacting the free base and acid in anorganic solvent, in which case the salt separates directly or can beobtained by concentration of the solution.

The compounds of this invention may also exist in hydrated or solvatedforms.

The products of the reactions described herein are isolated byconventional means such as extraction, distillation, chromatography andthe like.

The antiallergic and antiinflammatory activity of the compounds havingthe formula I of the present invention is determined by an assay showinginhibition of the release of histamine from human basophils (HHB). Adescription of the protocol of the HHB assay is found hereinafter.

Thus, pharmaceutical compositions are prepared from the compounds offormula I and salts thereof described as the present invention in unitdosage form comprising the compound either alone or in admixture with apharmaceutically acceptable carrier appropriately selected from thoseknown.

A physician or veterinarian of ordinary skill readily determines asubject who is exhibiting allergic or inflammatory symptoms. Regardlessof the route of administration selected, the compounds of the presentinvention are formulated into pharmaceutically acceptable dosage formsby conventional methods known to the pharmaceutical art.

The compounds can be administered in such oral unit dosage forms such astablets, capsules, pills, powders, or granules. They also may beadministered rectally or vaginally in such forms as suppositories orbougies; they may also be introduced parenterally (e.g., subcutaneously,intravenously, or intramuscularly), using forms known to thepharmaceutical art. They are also introduced directly to an affectedarea (e.g., in the form of eye drops or by inhalation). For thetreatment of allergic or inflammatory conditions such as erythema, thecompounds of the present invention may also be administered topically inthe form of ointments, creams, gels, or the like. In general, thepreferred route of administration is orally.

An effective but nontoxic quantity of the compound I is employed intreatment. The ordinarily skilled physician or veterinarian will readilydetermine and prescribe the effective amount of the antiallergic orantiinflammatory agent to prevent or arrest the progress of thecondition. The dosage regimen is selected in accordance with a varietyof factors including the type, age, weight, sex, and medical conditionof the mammal, the severity of symptoms of the disease being treated,the route of administration and particular compound of formula Iemployed. An ordinarily skilled physician or veterinarian will readilydetermine and prescribe the effective amount of the compound I toprevent or arrest the progress of the condition. In so proceeding, thephysician or veterinarian could employ relatively low dosages at first,subsequently increasing the dose until a maximum response is obtained.For convenience, the total daily dosage may be divided and administeredin portions during the day if desired. In so proceeding, the physicianor veterinarian could employ relatively low dosages at first,subsequently increasing the dose until a maximum response is obtained.

Initial dosages of the compounds of the invention having formula I areordinarily in the area of 10 mg up to 2 g per day orally, preferably 20mg to 500 mg per dose orally, given from one to four times daily or asneeded. When other forms of administration are employed, equivalentdoses are administered.

A suitable dose of a compound of formula (I) or pharmacologicallyacceptable salt thereof for a mammal suffering from, or likely to sufferfrom any condition as described hereinbefore is 0.1 μg-500 mg of thecompound per kilogram body weight. In the case of systemicadministration, the dose may be in the range of 0.5 to 500 mg of thecompound per kilogram body weight, the most preferred dosage being 0.5to 50 mg/kg of mammal body weight administered two or three times daily.In the case of topical administration, e.g., to the skin or eye, asuitable dose may be in the range 0.1 ng-100 μg of the compound perkilogram, typically about 0 1 μg/kg.

In the case of oral dosing for the treatment or prophylaxis of arthritisor inflammation in general, due to any course, a suitable dose of acompound of formula (I) or physiologically acceptable salt thereof, maybe as specified in the preceding paragraph, but most preferably is from1 mg to 10 mg of the compound per kilogram, the most preferred dosagebeing from 1 mg to 5 mg/kg of mammal body weight, for example, from 1 to2 mg/kg.

It is understood that the compositions and methods of treatment of thepresent invention as described above also include the free acid, thepharmacologically acceptable base salts and acid addition salts of thecompounds of formula I.

The following Examples further illustrate the invention, but are notmeant to be limiting thereto.

EXAMPLE 1 5-[(2,3-Dimethoxyphenyl)methylene]-2-thioxo-4-thiazolidinone

A mixture of 2,3-dimethoxybenzaldehyde (5.2 g, 30 mmoles), rhodanine(4.0 g, 29 mmoles), sodium acetate (8.4 g, 102 mmoles), and acetic acid(50 ml) is stirred under an inert atmosphere and heated to reflux. After4 hours the mixture is stirred into water (250 ml) and the precipitateis filtered off, rinsed successively with water (3×), ethanol (2×), andether (2×), and dried to afford the pure product (7.8 g), mp 268°-269°C.

                  TABLE 1                                                         ______________________________________                                        The following examples are prepared from the corresponding                    benzaldehydes using the procedure described in Example 1.                      ##STR19##                                                                    Example                                                                              R.sub.1                                                                              R.sub.2  R.sub.3                                                                            R.sub.4                                                                            mp °C.                                ______________________________________                                         2     OMe    H        OMe  H    275-276                                       3     OMe    H        H    OMe  245-246                                       4     OMe    OMe      OMe  H    205-206                                       5     OMe    H        OMe  OMe  297 (dec)                                     6     H      OMe      OMe  OMe  200-201                                       7     Cl     H        Cl   H    234-235                                                                              (Recryst.                                                                     from DMF)                              8     H      Cl       Cl   H    241-242                                       9     H      OMe      OMe  H    232-234                                      10     H      OMe      OH   OMe  252-253                                                                              (Recryst.                                                                     from MeOH)                            11     H      F        OMe  H    264-265                                      12     H      OH       OH   H    >300                                         13     H      Br       OH   H    283-285                                                                              (Recryst.                                                                     from EtOH)                            14     H      Br       OH   Br   >300                                         15     H      Me       OH   Me   293-295                                      16     H      OMe      OH   Br   275 (dec)                                    17     H      H        H    H    204-205                                      18     MeO    H        H    H    249-250                                      19     H      MeO      H    H    232-233                                      20     H      H        MeO  H    250-251                                      21     H      OH       H    H    246-248                                      22     H      H        OH   H    288 (dec)                                    23     H      OEt      H    H    170-172                                      24     H      OCHMe.sub.2                                                                            H    H    191-193                                      25     H      OCH.sub.2 Ph                                                                           H    H    197-198                                      26     H      Me       H    H    198-200                                      27     H      CF.sub.3 H    H    189-190                                      28     H      Cl       H    H    233-235                                      29     H      Br       H    H    239-241                                      30     H      NO.sub.2 H    H    265-267                                      31     H      H        Cl   H    224-226                                      32     H      H        Br   H    236-238                                      33     H      H        OPh  H    150-151                                      34     H      H        NO.sub.2                                                                           H    265-267                                      35     H      H        SMe  H    258-260                                      36     H      MeO      OH   H    229-230                                      37     H      MeO      H    MeO  257-259                                      38     H      H        Me   H    225- 227                                     39     H      H        Ph   H    240-242                                      ______________________________________                                    

EXAMPLE 40 5-[(2,3-Dichlorophenyl)methylene]-2-thioxo-4-thiazolidinone

A mixture of 2,3-dichlorobenzaldehyde (4.6 g, 26 mmoles), rhodanine (3.5g, 25 mmoles), sodium acetate (7.5 g, 91 mmoles), and acetic acid (40ml) is stirred under an inert atmosphere and heated to reflux. After 2.5hours the mixture is stirred into ice-water (250 ml) and the precipitateis filtered off, rinsed three times with water and dried.Recrystallization from methanol gave the pure product (2.9 g), mp203°-204° C.

The following examples are prepared from the corresponding benzaldehyesusing the procedure described in Example 40:

    ______________________________________                                                                                   Recryst.                           Example                                                                              R.sub.1                                                                              R.sub.2                                                                              R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            mp °C.                                                                        Solvent                            ______________________________________                                        41     Cl     H      H    H    Cl   179-181                                                                              --                                 42     H      tBu    OH   tBu  H    248-249                                                                              EtOAc                              43     H      F      H    H    H    201-202                                                                              MeCN                               44     OH     H      H    H    H    216 (dec)                                                                            MeCN                               45     H      OH     OMe  H    H    224-225                                                                              MeOH                               46     H      iPr    OH   iPr  H    200-202                                                                              MeCN                               47     H      OH     OMe  OMe  H    212-213                                                                              MeOH                               48     OMe    H      H    H    OMe  273-275                                                                              DMF                                49     OH     H      H    OMe  H    253 (dec)                                                                            --                                 50     H      OH     H    OMe  H    259-260                                                                              THF                                51     H      OMe    OH   tBu  H    233-234                                                                              MeCN                               52     OH     H      OMe  OMe  H    258 (dec)                                 ______________________________________                                    

EXAMPLE 535-[[3-[(Dimethylamino)methyl]-4-hydroxy-5-methoxyphenyl]methylene]-2-thioxo-4-thiazolidinone

A mixture of 3-[(dimethylamino)methyl]-4-hydroxy-5-methoxybenzaldehyde(2.5 g, 12 mmoles), rhodanine (1.6 g, 12 mmoles), β-alanine (0.6 g, 7mmoles), and acetic acid (35 ml) is stirred under an inert atmosphereand heated to reflux. After 4 hours the acetic acid is removed by rotaryevaporator and the residue dissolved in water (250 ml). The solution isbrought to approximate neutrality by addition of saturated aqueoussodium bicarbonate, and stirred for 3 hours. The precipitate is filteredoff, rinsed three times with water and dried, then triturated in boilingmethanol (100 ml), cooled, filtered off and dried to afford the pureproduct (2.9 g), mp 198° C. (dec).

EXAMPLE 54 5-[(5-Bromo-2-thienyl)methylene]-2-thioxo-4-thiazolindinone

Prepared by the method described in Example 1 from5-bromo-2-thiophenecarboxaldehyde, mp 250°-252° (dec).

INTERMEDIATE A N,6-Dimethoxy-N-methyl-2-benzofurancarboxamide

To a stirred solution of 6.0 g (0.031 mole) of6-methoxy-2-benzofurancarboxylic acid (A. McGookin, A. Robertson, and W.B. Whalley, J. Chem. Soc. 787 (1940)) in 100 ml of tetrahydrofuran(under a nitrogen atmosphere) was added in one portion, 3.3 ml (4.8 g;0.038 mole) of oxalyl chloride. The mixture was stirred for 5 minutes,then treated with 3 drops of N,N-dimethylformamide. After stirring atroom temperature for 2 hours, the solvent was evaporated to leave aresidue of crude 6-methoxy-2-benzofurancarbonyl chloride, mp 96°-99° (amp of 101° is given by A. McGookin, etc., cited above). The residue wasre-dissolved in 100 ml of dichloromethane, and the solution wasfiltered. The filtrate was added dropwise over 20 minutes to anice-cooled solution of 3.6 g (0.037 mole) of N,0-dimethylhydroxylaminehydrochloride and 9.4 ml (7.7 g; 0.077 mole) of 1-methylpiperidine in100 ml of dichloromethane. After stirring for 2 hours, the mixture wasadded to 400 ml of ice-cold 5% aqueous hydrochloric acid. The layerswere separated, and the aqueous layer was extracted with freshdichloromethane (3× 100 ml). The combined organic layers were washedwith water (1× 200 ml), 3% aqueous sodium bicarbonate (2× 200 ml), andwater again. The extracts were dried (anhydrous magnesium sulfate) andevaporated. Trituration of the residue with ether yielded 5.4 g (74%yield) of the analytically pure amide product, mp 73°-77°.

Calcd. for C₁₂ H₁₃ NO₄ : C, 61.27; H, 5.57; N, 5.96. Found: C, 61.26; H,5.52; N, 5.78.

INTERMEDIATE B 6-Methoxy-2-benzofurancarboxaldehyde

An ice-cooled solution of 4.0 g (0.017 mole) ofN,6-dimethoxy-N-methyl-2-benzofurancarboxamide in 100 ml oftetrahydrofuran was treated cautiously over 15 minutes (under a nitrogenatmosphere) with 0.65 g (0.017 mole) of lithium aluminum hydride. Themixture was stirred for 1 hour, then quenched by the careful addition of100 ml of saturated aqueous sodium bisulfate solution. The reactionmixture was extracted with ether (3× 75 ml), and the combined extractswere washed with cold 2% aqueous hydrochloric acid (2× 100 ml), followedby brine (1× 100 ml). The organic layer was dried (anhydrous magnesiumsulfate) and evaporated. The residue was chromatographed (silica gel,dichlormethane elution) to yield 2.2 g (74% yield) of the analyticallypure aldehyde, mp 75°-77°.

Calcd. for C₁₀ H₈ O₃ : C, 68.18; H, 4.58. Found: C, 68.03; H, 4.48.

EXAMPLE 555-[(6-Methoxy-2-benzofuranyl)methylene]-2-thioxo-4-thiazolidinone

A mixture of 1.5 g (0.0085 mole) of6-methoxy-2-benzofurancarboxaldehyde, 1.1 g (0.0083 mole) of2-thioxo-4-thiazolidinone ("rhodanine"), and 2.5 g (0.030 mole) ofanhydrous sodium acetate in 40 ml of glacial acetic acid (under anitrogen atmosphere) was stirred and heated at reflux for 5 hours. Thecooled mixture was added to 250 g of ice/water. The precipitated solidwas filtered, washed with water, then with a little cold ethanol toyield 2.0 g (81% yield) of the analytically pure thiazole, mp >290°.

Calcd. for C₁₃ H₉ NO₃ S₂ : C, 53.59; H, 3.11; N, 4.81; S, 22.01. Found:C, 53.82; H, 3.08; N, 5.15; S, 21.71.

The following Examples are for compounds also prepared by the proceduresdescribed the preparation of intermediates A and B and Example 55 above.

EXAMPLE 565-[(5-Methoxy-2-benzofuranyl)methylene]-2-thioxo-4-thiazolidinone

mp 261°-263° (recrystallized from acetonitrile/N,N-dimethylformamide).

Clcd. for C₁₃ H₉ NO₃ S₂ : C, 53.59; H, 3.11; N, 4.81; S, 22.01. Found:C, 53.68; H, 3.23; N, 4.87; S, 21.88.

The starting carboxylic acid was 5-methoxy-2-benzofurancarboxylic acid(W. B. Whalley, J. Chem. Soc., 3479 (1953)).

EXAMPLE 57 5-[(Benzo[b]thien-2-yl)methylene]-2-thioxo-4-thiazolidinone

mp 245°-dec (recrystallized from acetonitrile/N,N-dimethylformamide).

Calcd. for C₁₂ H₇ NOS₃ : C, 51.96; H, 2.54; N, 5.05; S, 34.68. Found: C,51.87; H, 2.41; N, 5.13; S, 34.45.

The starting carboxylic acid was commercially availablebenzo[b]thiophene-2-carboxylic acid.

EXAMPLE 585-[[5-Methoxy-3-(1-methylethoxy)benzob]thien-2-yl]methylene]-2-thioxo-4-thiazolidinone

mp 242°-dec.

Calcd. for C₁₆ H₁₅ NO₃ S₃ : C, 52.58; H, 4.14; N, 3.83; S, 26.32. Found:C, 53.00; H, 4.13; N, 3.75; S, 25.95.

The starting carboxylic acid was3-(1-methylethoxy)-5-methoxy-benzo[b]thiophene-2-carboxylic acid (D. T.Connor, W. A. Cetenko, P. C. Unangst, and E. A. Johnson, U.S. Pat. No.4,703,053.

EXAMPLE 595-[(5-Methoxy-1-phenyl-1H-indol-2-yl)methylene]-2-thioxo-4-thiazolidinoine

mp 250°-253° (recrystallized from aqueousacetonitrile/N,N-dimethylformamide).

Calcd. for C₁₉ H₁₄ N₂ O₂ S₂.1H₂ O: C, 59.35; H, 4.19; N, 7.29; S, 16.68.Found: C, 59.56; H, 4.03; N, 7.06; S, 16.02.

The starting carboxylic acid was5-methoxy-1-phenyl-lH-indole-2-carboxylic acid (P. C. Unangst, D. T.Connor, S. R. Stabler, and R. J. Weikert, J. Heterocyclic Chem., 24, 811(1987)).

EXAMPLE 605-[(5-Methoxy-1-phenyl-1H-indol-2-yl)methylene]-2-thioxo-4-thiazolidinone,1-methylpiperidine salt

A suspension of 3.0 g (0.0082 mole) of 5-(5-methoxy1-phenyl-1H-indol-2-yl)methylene]-2-thioxo-4-thiazolidinone in 50 ml ofmethanol was treated with 1.1 ml (0.89 g; 0.0090 mole) of1-methylpiperidine. The mixture was stirred briefly on the steam bathuntil homogeneous and filtered warm. Cooling to room temperatureovernight yielded 3.2 g (84% yield) of the crystalline, analyticallypure salt, mp 188°-191°.

Calcd. for C₁₉ H₁₄ N₂ O₂ S₂.C₆ H₁₃ N: C, 64.48; H, 5.84; N, 9.03; S,13.77. Found: C, 64.02; H, 5.81; N, 8.82; S, 13.42.

EXAMPLE 61 5-[(5-Bromo-2-thienyl)methylene]-2-thioxo-4-thiazolidinone,monsodium salt

A suspension of 2.0 g (0.0065 mole) of5-[(5-bromo-2-thienyl)methylene-2-thioxo-4-thiazolidinone in 25 ml ofethanol was treated with 3.3 ml of 2.00N aqueous sodium hydroxidesolution. The mixture was warmed on the steam bath until homogeneous andfiltered warm. Cooling yielded 1.2 g (56% yield) of the analyticallypure salt, mp 288°-dec.

Calcd. for C₈ H₃ BrNOS₃ Na.1.5 H₂ O: C, 27.05; H, 1.70; N, 3.94. Found:C, 27.06; H, 1.66; N, 3.70.

EXAMPLE 625-[(3-Bromo-4-hydroxy-5-methoxyphenyl)methylene]-2-thioxo-4-thiazolidinone,disodium salt

A suspension of 3.46 g (0.010 mole) of5-[(3-bromo-4-hydroxy-5-methoxyphenyl)methylene-2-thioxo-4-thiazolidinonein 50 ml of water was treated with 10.0 ml of 2.00N aqueous sodiumhydroxide solution. The mixture was warmed on the steam bath untilnearly homogenous and filtered warm. The cooled filtrate was subjectedto vacuum freeze-drying to leave a residue of 3.8 of red solid. Thesolid was digested briefly on the steam bath with 200 ml of acetone.Filtration gave 3.5 g (88% yield) of the analytically pure salt, mp>310°.

Calcd. for C₁₁ H₆ BrNO₃ S₂ Na₂.0.5 H₂ O: C, 33.09; H, 1.77; N, 3.51.Found: C, 33.03; H, 1.73; N, 3.36.

EXAMPLE 635-[(4-Hydroxy-3,5-dimethoxyphenyl)methylene]-2,4-thiazolidinedione

Prepared according to the procedure described in Example 1 using3,5-dimethoxy-4-hydroxybenzaldehyde (4.8 g, 20 mmoles) and2,4-thiazolidinedione (2.9 g, 25 mmoles). Recrystallization frommethanol gave the pure product (1.7 g), mp 248°-249° C.

EXAMPLE 645-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2,4-thiazolidinedione

A mixture of 3,5-di-t-butyl-4-hydroxybenzaldehyde (6.5 g, 27 mmoles),2,4-thiazolidinedione (3.0 g, 26 mmoles), sodium acetate (7.6 g, 93mmoles), and acetic acid (40 ml) is stirred under an inert atmosphereand heated to reflux. After 78 hours the mixture is stirred into water(300 ml), and the precipitate is filtered off, rinsed three times withwater, dried, and recrystallized from ethanol. The product is stirred in1N NaOH (50 ml) and extracted several times with dichloromethane. Theaqueous solution is acidified with acetic acid, stirred for 1-2 hours,and the precipitate is filtered off, rinsed three times with water anddried to afford the pure product (2.3 g), mp 238°-240° C.

The following compounds are prepared by the method described in Example64:

    ______________________________________                                         ##STR20##                                                                    Example       R          MP                                                   ______________________________________                                        65            H          247-249                                              66            3-OMe      197-198                                              67            4-OMe      218-220                                              68            3-OMe, 4-OH                                                                              225-227                                              ______________________________________                                    

INTERMEDIATE C 2-Thioxo-4-oxazolidinone

A solution of 72.9 g (0.75 mole) of potassium thiocyanate and 48.9 g(0.75 mole) of potassium cyanide in 85 ml of water was stirred in an icebath and treated over 30 minutes with 60 ml (˜0.80 mole) of 37% aqueousformaldehyde solution. The rate of addition was adjusted to maintain areaction temperature of ≦10°. The mixture was stirred for an additional90 minutes, then treated over 1 hour with 156 ml of concentratedhydrochloric acid (reaction temperature maintained at ≦10°). The mixturewas stirred for 16 hours as it slowly warmed to room temperature. Theinorganic solids were filtered and discarded, and the filtrate waswarmed on the steam bath for 90 minutes. The reaction mixture was againfiltered, and the filtrate was extracted with ether (5× 200 ml). Thecombined extracts were dried (anhydrous sodium sulfate) and evaporatedto an oil, which slowly crystallized. The solid was washed with hexaneto yield 22.7 g (26% yield), mp 106°-109°. A sample recrystallized fromethyl acetate/hexane was analytically pure, mp 110°-112° (a mp of 113°is given by N. K. Ushenko and T. E. Gorizdra, Ukrain. Khim. Zhur., 16,545 (1950)).

EXAMPLE 695-[(4-Hydroxy-3-methoxyphenyl)methylene]-2-thioxo-4-oxazolidinone

A mixture of 3.25 g (0.021 mole) of 4-hydroxy-3-methoxybenzaldehyde,2.34 g (0.020 mole) of 2-thioxo-4-oxazolidinone, 5.8 g (0.071 mole) ofsodium acetate and 15 ml of acetic acid was stirred and heated at refluxunder a nitrogen atmosphere for 2 hours. The mixture was then stirred atroom temperature for 16 hours, and added to 300 g of ice/water. Theprecipitated solid was filtered, washed with water, and recrystallizedfrom aqueous methanol/N,N-dimethylformamide to yield 2.4 g (49% yield)of the oxazole product. A sample recrystallized a second time as abovewas analytically pure, mp 240°-dec. (A mp of 237°-238° is given by T. E.Gorizdra and S. N. Baranov, Zhur. Obshchei Khim., 26, 3092 (1956)).

Calcd. for C₁₁ H₉ NO₄ S.0.25H₂ O: C, 51.65; H, 3.74; N, 5.48; S, 12.54.Found: C, 51.54; H, 3.97; N, 5.38; S, 12.17.

Also prepared by the procedure described in Example 69, utilizing theappropriate aldehyde intermediate were:

EXAMPLE 70 5-[(3-Methoxyphenyl)methylene]-2-thioxo-4-oxazolidinone

mp 215°-dec (recrystallized from methanol (N,N-dimethylformamide).

Calcd. for C₁₁ H₉ NO₃ S: C, 56.15; H, 3.86; N, 5.95; S, 13.63. Found: C,56.34; H, 3.87; N, 5.95; S, 13.51.

EXAMPLE 71 5-[(4-Methoxyphenyl)methylene]-2-thioxo-4-oxazolidinone

mp 205°-207° (recrystallized from aqueousmethanol/N,N-dimethylformamide). (A mp of 192° is given by N. K. Ushenkoand T. E. Gorizdra, Ukrain Khim. Zhur., 16, 545 (1950)).

Calcd. for C₁₁ H₉ NO₃ S: C, 56.15; H, 3.86; N, 5.95; S, 13.63. Found: C,56.10; H, 3.88; N, 6.03; S, 13.62.

EXAMPLE 72 5-[(3,4-Dimethoxyphenyl)methylene]-2-thioxo-4-oxazolidinone

mp 249°-dec.

Calcd. for C₁₂ H₁₁ NO₄ S: C, 54.32; H, 4.18; N, 5.28; S, 12.09. Found:C, 53.92; H, 4.10; N, 5.22; S, 11.84.

EXAMPLE 735-[(4-Hydroxy-3,5-dimethoxyphenyl)methylene]-2-thioxo-4-oxazolidinone

mp 250°-dec. (recrystallized from aqueousacetonitrile/N,N-dimethylformamide).

Calcd for C₁₂ H₁₁ NO₅ S: C, 51.24; H, 3.94; N, 4.98; S, 11.40. Found: C,51.00; H, 3.78; N, 5.30; S, 11.45.

EXAMPLE 745-[(4-Hydroxy-3,5-dimethylphenyl)methylene]-2-thioxo-4-oxazolidinone

mp 253°-dec.

Calcd. for C₁₂ H₁₁ NO₃ S: C, 57.81; H, 4.45; N, 5.62; S, 12.86. Found:C, 57.84; H, 4.49; N, 5.56; S, 12.54.

EXAMPLE 755-[(3-Bromo-4-hydroxy-5-methoxyphenyl)methylene]-2-thioxo-4-oxazolidinone

mp 260°-262°

Calcd. for C₁₁ H₈ BrNO₄ S: C, 40.01; H, 2.44; N, 4.24; S, 9.71; Br,24.20. Found: C, 40.18; H, 2.34; N, 4.07; S, 9.61; Br, 24.02.

EXAMPLE 762-Thioxo-5-[(2,4,5-trimethoxyphenyl)methylene]-4-oxazolidinone

mp 265°-dec. (recrystallized from aqueousmethanol/N,N-dimethylformamide).

Calcd. for C₁₃ H₁₃ NO₅ S: C, 52.87; H, 4.44; N, 4.74; S, 10.86. Found:C, 52.55; H, 4.30; N, 4.79; S, 10.47.

EXAMPLE 772-Thioxo-5-[(3,4,5-trimethoxyphenyl)methylene]-4-oxazolidinone

mp 230°-dec. (recrystallized from aqueousmethanol/N,N-dimethylformamide).

Calcd. for C₁₃ H₁₃ NO₅ S: C, 52.87; H, 4.44; N, 4.74; S, 10.86. Found:C, 52.81; H, 4.32; N, 4.62; S, 10.39.

EXAMPLE 785-[(4-Hydroxy-3,5-dimethoxyphenyl)methylene]-2-thioxo-4-oxazolidinone,disodium salt

A suspension of 3.1 g (0.011 mole) of5-(4-hydroxy-3,5-dimethoxyphenyl)methylene]-2-thioxo-4-oxazolidinone in20 ml of water was treated with a solution of 11.0 ml of 2.00N aqueoussodium hydroxide solution. The mixture was warmed briefly on the steambath until nearly homogenous, then filtered warm. The cooled filtratewas subjected to vacuum freeze-drying to yield 3.5 g (98% yield) of theanalytically pure salt product, mp >265°.

Calcd. for C₁₂ H₉ NO₅ SNa₂.0.6 H₂ O: C, 42.89; H, 3.06;N, 4.17. Found:C, 42.67; H, 2.88;N, 4.00.

Also prepared by the above procedures was:

EXAMPLE 795-[(4-Hydroxy-3-methoxyphenyl)methylene]-2-thioxo-4-oxazolidinone,disodium salt

mp >270°

Calcd. for C₁₁ H₇ NO₄ SNa₂.1 H₂ O: C, 42.18; H, 2.90; N, 4.47. Found: C,41.84; H, 2.52;N, 4.37.

EXAMPLE 805-[(3,5-Dibromo-4-hydroxyphenyl)methylene]-2-thioxo-4-imidazolidinone

Prepared according to the procedure described in Example 1 using3,5-dibromo-4-hydroxybenzaldehyde (4.5 g, 16 mmoles), 2-thiohydantoin(1.7 g, 15 mmoles), sodium acetate (4.5 g, 55 mmoles), and acetic acid(35 ml). Recrystallization from ethanol gave the pure product (1.4 g),mp 267° C. (dec).

EXAMPLE 815-[[4-hydroxy-3,5-bis(1-methylethyl)phenyl]methylene]-2-thioxo-4-imidazolidinone

Prepared according to the procedure described in Example 1 using4-hydroxy-3,5-bis(1-methylethyl)benzaldehyde (3.0 g, 15 mmoles),2-thiohydantoin (1.6 g, 14 mmoles), sodium acetate (4.2 g, 51 mmoles),and acetic acid (35 ml), filtered off, dried, and recrystallized fromacetonitrile to afford the pure product (1.4 g), mp 225°-230° C.

EXAMPLE 825-[(3-Bromo-4-hydroxyphenyl)methylene]-2-thioxo-4-imidazolidinone

Prepared according to the procedure described in Example 1 using3-bromo-4-hydroxybenzaldehyde (3.1 g, 15 mmoles), 2-thiohydantoin (1.7g, 15 mmoles), sodium acetate (4.5 g, 55 mmoles), and acetic acid (35ml), to afford the pure product (3.4 g), mp 262° C. (dec).

EXAMPLE 835-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-imidazolidinone

Prepared according to the procedure described in Example 1 using3,4-di-t-butyl-4-hydroxybenzaldehyde (6.2 g, 26 mmoles), 2-thiohydantoin(2.9 g, 25 mmoles), sodium acetate (7.5 g, 91 mmoles), and acetic acid(40 ml). Heating under reflux is maintained for 36 hours.Recrystallization from acetonitrile gave the pure product (4.0 g), mp279°-281° C. (dec).

EXAMPLE 84 5-[(2-Methoxyphenyl)methylene]-2-thioxo-4-imidazolidinone

A mixture of 2-methoxybenzaldehyde (2.5 g, 18 mmoles), 2-thiohydantoin(2.0 g, 17 mmoles), sodium acetate (4.0 g, 49 mmoles), acetic anhydride(1/2 ml), and acetic acid (15 ml) is stirred under an inert atmosphereand heated to reflux. After 1 hour the mixture is stirred into water(300 ml), and the precipitate is filtered off, rinsed with water threetimes and dried. The product is triturated in boiling methanol, filteredoff, and dried to afford the pure product (3.4 g), mp 234°-235° C.

The following examples are prepared from the corresponding benzaldehydesusing the procedure described in Example 84.

    ______________________________________                                         ##STR21##                                                                                                            Recryst.                              Example   R.sub.1                                                                              R.sub.2  R.sub.3                                                                            mp °C.                                                                          Solvent                               ______________________________________                                        85        OMe    H        H    238-239  MeOH                                  86        H      OMe      H    266-267  MeOH                                  87        OMe    OH       H    237-238  MeCN                                  88        OMe    OH       OMe  268 (dec)                                                                              MeOH                                  ______________________________________                                    

EXAMPLE 895-[[4-(Acetyloxy)-3-methoxyphenyl]methylene]-2,4-imidazolidinedione

Prepared according to the procedure described in Example 84, using4-acetoxy-3-methoxybenzaldehyde (4.0 g, 21 mmoles) and hydantoin (2.0 g,20 mmoles). Recrystallization from methanol/DMF gave the product (1.8g), mp 275°-277° C., retaining 0.15 equivalents of DMF.

EXAMPLE 905-[(4-Hydroxy-3-methoxyphenyl)methylene]-2,4-imidazolidinedione

A mixture of 4-hydroxy-3-methoxybenzaldehyde (4.6 g, 30 mmoles),hydantoin (3.0 g, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and aceticacid (40 ml) is stirred under an inert atmosphere and heated to reflux.After 4 hours the mixture is stirred into water (350 ml) and theprecipitate is filtered off, rinsed successively with water (3×),ethanol (2×), and ether (2×), and dried. Recrystallization from methanolafforded the pure product (3.0 g), mp 272°-273° C.

EXAMPLE 915-[(3,5-Dimethoxy-4-hydroxyphenyl)methylene]-2,4-imidazolidinedione

Prepared according to the procedure described in Example 90 using3,5-dimethoxy-4-hydroxybenzaldehyde (5.6 g, 30 mmoles), hydantoin (3.0g, 30 mmoles), and β-alanine (1.4 g, 16 mmoles), to afford the pureproduct (6.0 g), mp 296°-297° C.

EXAMPLE 925-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2,4-imidazolidinedione

A mixture of 3,5-di-t-butyl-4-hydroxybenzaldehyde 7.0 g, 30 mmoles),hydantoin (3.0 g, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and aceticacid (40 ml) is stirred under an inert atmosphere and heated to reflux.After 48 hours the mixture is stirred into water (300 ml), and theprecipitate is filtered off, rinsed with water three times, and dried.Recrystallization from acetonitrile gave the pure product (4.8 g), mp251°-252° C.

EXAMPLE 935-[(2-Methoxyphenyl)methylene]-3-methyl-2,4-imidazolidinedione

A mixture of 2-methoxybenzaldehyde (3.4 g,25 mmoles), 3-methyl hydantoin(3.0 g, 21 mmoles), sodium acetate (6.0 g, 73 mmoles), acetic anhydride(3 ml), and acetic acid (20 ml) is stirred under an inert atmosphere andheated to reflux. After 15 hours the mixture is poured into water (200ml), stirred, and the precipitate filtered off, rinsed three times withwater and dried. Recrystallization from acetonitrile gave the pureproduct (3.1 g), mp 189°-190° C.

EXAMPLE 945-[(3-Methoxyphenyl)methylene]-3-methyl-2,4-imidazolidinedione

Prepared according to the procedure described in Example 93 using3-methoxybenzaldehyde (3.5 ml, 28 mmoles) and 3-methyl hydantoin (3.0 g,21 mmoles), to afford the product (3.6 g), mp 203°-205° C.

EXAMPLE 955-[(4-Methoxyphenyl)methylene]-3-methyl-2,4-imidazolidinedione

Prepared according to the procedure described in Example 93 using4-methoxybenzaldehyde (3.4 g, 25 mmoles) and 3-methyl hydantoin (3.0 g,21 mmoles). Recrystallization from acetonitrile gave the pure product(2.0 g), mp 221°-222° C.

EXAMPLE 965-[(4-Hydroxy-3-methoxyphenyl)methylene]-3-methyl-2,4-imidazolidinedione

Prepared according to the procedure described in Example 93 using4-hydroxy-3-methoxybenzaldehyde (3.2 g, 21 mmoles) and 3-methylhydantoin (3.0 g, 21 mmoles). Recrystallization from ethyl acetate gavethe pure product (0.7 g), mp 227°-228° C.

EXAMPLE 975-[(3,5-Dimethoxy-4-hydroxyphenyl)methylene]-3-methyl-2,4-imidazolidinedion

A mixture of 3,5-dimethoxy-4-hydroxybenzaldehyde (3.2 g, 18 mmoles),3-methyl hydantoin (2.0 g, 18 mmoles), sodium acetate (6.0 g, 73mmoles), acetic anhydride (3 ml), and acetic acid (25 ml) is stirredunder an inert atmosphere and heated to reflux. After 72 hours themixture is stirred into water (300 ml) and the precipitate is filteredoff, rinsed three times with water and dried to give a product (4.0 g)which is a mixture of the desired product and its O-acetate. A mixtureof this product (2.1 g), sodium carbonate (3.5 g), DMSO (5 ml), andmethanol (50 ml) is stirred and heated to reflux. After 18 hours themixture is stirred into icewater (400 ml) and acidified with 4N HCl. Theprecipitate is filtered off, rinsed successively with water (3×),ethanol (2×), and ether (2×), and dried. Recrystallization frommethanol/DMF gave the pure product (0.6 g), mp 269°-270° C.

EXAMPLE 985-[(3-Methoxyphenyl)methylene]-1-methyl-2,4-imidazolidinedione

A mixture of 2-methoxybenzaldehyde (3.8 g, 28 mmoles), 1-methylhydantoin (3.0 g 26 mmoles), sodium acetate (8.4 g, 102 mmoles), aceticanhydride (10 ml), and acetic acid (40 ml) is stirred under an inertatmosphere and heated to reflux. After 24 hours the mixture is stirredinto water (350 ml), stirred, and the resulting gum is isolated andwashed by decantation, then crystallized from isopropanol.Recrystallization from acetonitrile gave the pure product (1.1 g), mp195°-197° C.

EXAMPLE 995-[(4-Hydroxy-3-methoxyphenyl)methylene]-1-methyl-2,4-imidazolidinedione

A mixture of 4-hydroxy-3-methoxybenzaldehyde (4.6 g, 30 mmoles),1-methyl hydantoin (3.5 g, 30 mmoles), β-alanine (1.4 g, 16 mmoles), andacetic acid (40 ml) is stirred under an inert atmosphere and heated toreflux. After 8 hours the mixture is stirred into water (300 ml) and theprecipitate filtered off, rinsed successively with water (3×), ethanol(2×), and ether (2×) and dried. Recrystallization from acetonitrile gavethe pure product (1.1 g), mp 197°-198° C.

EXAMPLE 1005-[(3,5-Dimethoxy-4-hydroxyphenyl)methylene]-1-methyl-2,4-imidazolidinedione

Prepared according to the procedure described in Example 99 using3,5-dimethoxy-4-hydroxybenzaldehyde (5.8 g, 31 mmoles) and 1-methylhydantoin (3.5 g, 30 mmoles). Recrystallization from ethanol gave thepure product (2.8 g),mp 194°-196° C.

EXAMPLE 1015-[(3,5-Dibromo-4-hydroxyphenyl)methylene]-1-methyl-2,4-imidazolidinedione

Prepared according to the procedure described in Example 99 using3,5-dibromo-4-hydroxybenzaldehyde (8.4 g, 30 mmoles) and 1-methylhydantoin (3.5 g, 30 mmoles) to afford the pure product (8.2 g), mp271°-277° C.

EXAMPLE 1025-[[4-Hydroxy-3,5-bis(1-methylethyl)phenyl]methylene]-1-methyl-2,4-imidazolidinedione

Prepared according to the procedure described in Example 92 using3,5-diisopropyl-4-hydroxybenzaldehyde (2.7 g, 13 mmoles) and 1-methylhydantoin (1.4 g, 12 mmoles). Recrystallization from acetonitrile gavethe pure product (0.4 g), mp 197°-208° C.

The following compounds are prepared according to the proceduredescribed in Example 1 using appropriate corresponding startingmaterials.

EXAMPLE 103

5-[(4-Pyridyl)methylene]-2-thioxo-4-thiazolidinone, mp >300°.

EXAMPLE 104

5-[(2-Thienyl)methylene-2-thioxo-4-thiazolidinone, mp 227°-229°.

EXAMPLE 105

5-[(5-Nitro-2™furanyl)methylene-2-thioxo-4-thiazolidinone, mp 201°-202°.

EXAMPLE 106

5-[(1-Phenyl-1H-indol-2-yl)methylene]-2-thioxo-4-thiazolidinone, mp282°-283°.

EXAMPLE 107

5-[(3-Bromo-4-hydroxyphenyl)methylene]-2-thioxo-4-oxazolidinone, mp 240°(dec). Prepared according to the procedure described in Example 69.

EXAMPLE 1085-[[3,5-Bis(1,1-dimethylethyl-4-hydroxyphenyl]methylene-2-thioxo-4-oxazolidinone

A mixture of 14.1 g (0.060 mole) of3,5-di-tert-butyl-4-hydroxybenzaldehyde, 7.0 g (0.060 mole) of2-thioxo-4-oxazolidinone, 17.4 g (0.21 mole) of sodium acetate, and 75ml of acetic acid is stirred and heated at reflux under a nitrogenatmosphere for 20 hours. The cooled reaction mixture is added to 900 gof ice/water and the precipitated product filtered and washed withwater. There is obtained 16.2 g (81% yield) of the oxazole product,suitable for further reaction.

A sample of the above crude product is chromatographed over silica gel,using elution with 2.5% ethyl acetate in dichloromethane followed by 25%ethyl acetate. The chromatography product is recrystallized from aqueousacetonitrile to yield the analytically pure oxazole, mp 240° C. dec.

Calcd. for C₁₈ H₂₃ NO₃ S: C, 64.83; H, 6.95;N, 4.20. Found: C, 65.00; H,6.95;N, 4,17.

EXAMPLE 1095-[[3,5-Bis(1,1-dimethylethyl-4-hydroxyphenyl]methylene]-2,4-oxazolidinedione

A solution of 10.0 9 (0.030 mole) of5-[[3,5-bis(1,1-dimethylethyl-4-hydroxyphenyl]methylene-2-thioxo-4-oxazolidinonein 150 ml of tetrahydrofuran is cooled in ice and treated with 4.2 ml(3.0 g, 0.030 mole) of triethylamine. The mixture is stirred with icecooling for one hour, then treated with 10.0 ml (22.8 g, 0.16 mole) ofiodomethane. The ice bath is removed and the mixture stirred for anadditional 24 hours. The reaction mixture is filtered and the filtercake is washed several times with fresh tetrahydrofuran. The combinedfiltrates are evaporated and the residue is chromatographed (silica gel,2% methanol in dichloromethane elution) to yield 4.4 g (42% yield) ofthe purified 2-methylthio- intermediate. This material is hydrolyzedwithout further purification.

A solution of 3.0 g (0.086 mole) of the above 2-methylthio-intermediatein 90 ml of ethanol is diluted with 30 ml of water and treated dropwiseover 10 minutes with 5.0 ml of concentrated hydrochloric acid. Thereaction mixture is stirred for 24 hours and the precipitated product isfiltered and washed with hexane. The crude yield is 1.44 g (53%). Asample recrystallized from ethyl acetate/hexane yielded the analyticallypure oxazolidinedione, mp 239° C. dec.

Calcd. for C₁₈ H₂₃ NO₄ : C, 68.12; H, 7.31;N, 4.41. Found: C, 68.22; H,7.29;N, 4.05.

Also prepared by the above procedure, utilizing the appropriate2-thioxo-4-oxazolidinone intermediate are:

EXAMPLE 1105-[(4-Hydroxy-3,5-dimethoxyphenyl)methylene]-2,4-oxazolidinedione

mp 268° dec. (recrystallized from acetonitrile/DMF/water).

Calcd for C₁₂ H₁₁ NO₆ : C, 54.34; H, 4.18;N, 5.28. Found: C, 54.00; H,4.17;N, 5.15.

EXAMPLE 1115-[(4-Hydroxy-3,5-dimethylphenyl)methylene]-2,4-oxazolidinedione

mp 275° C. dec. (recrystallized from acetonitrile/DMF/water).

Calcd. for C₁₂ H₁₁ NO₄.0.5H₂ O: C, 59.50; H, 4.99;N, 5.78. Found: C,59.31; H, S.02;N, 5.72.

EXAMPLE 1125-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-oxazolidinone,choline salt

A solution of 2.45 g (0.0069 mole) of 46.6% aqueous choline bicarbonatein 50 ml of methanol is stirred and treated over 5 minutes with 2.31 g(0.0069 mole) of5[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenylmethylene-2-thioxo-4-oxazolidinone.The reaction mixture is warmed for a few minutes to reflux on the steambath, and filtered hot. The cooled filtrate is evaporated, and theresidue recrystallized from acetone/tert-butyl methyl ether to yield 2.1g (70% yield) of the analytically pure choline salt, mp 167° dec.

Calcd. for C₂₃ H₃₆ N₂ O₄ S: C, 63.27; H, 8.31;N, 6.42. Found: C, 63.22;H, 8.21;N, 6.28.

EXAMPLE 1135-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2,4-thiazolidinedione,choline salt

A solution of 46.6% aqueous choline bicarbonate (10.55 g, 29.8 mmoles)is added dropwise under nitrogen to a stirred suspension of5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene)2,4-thiazolidinedione(10.0 g, 30.0 mmoles) in ethanol (100 ml). The solution is graduallywarmed to reflux for one hour, and is then cooled and stripped ofsolvent by rotary evaporator. Two 50-ml portions of ethanol aresuccessively mixed with and stripped from the residue which is thenthoroughly dried under vacuum. The residue is triturated in diethylether, filtered off, washed twice with ether, and dried under vacuum at80° C. overnight to afford the crystalline choline salt (12.8 g), mp215° C. dec.

Calcd. for C₁₈ H₂₂ NO₃ S.C₅ H₁₄ NO: C, 63.27; H, 8.31;N, 6.42. Found: C,63.12; H, 8.28;N, 6.17.

The usefulness of the compounds of the present invention as inhibitorsof histamine release is demonstrated by the following assay. The assayis essentially as generally accepted among the ordinarily skilledartisans to show activity having usefulness to treat the diseases orconditions as set out in the present invention. A description of theprocedure follows.

HISTAMINE RELEASE FROM HUMAN BASOPHILS (hereinafter HHB)

The HHB assay quantitates active histamine release, and its inhibitionby drugs, from basophils of human blood. Thus, the assay providesevaluation of the compounds of formula I for treating the conditions ordiseases as is the present invention. As described herein the assayincludes modifications of the method described by R. P. Siraganian in"An Automated Continuous-Flow System for the Extraction and FluorometricAnalysis of Histamine", Anal. Biochem., 57, 383-394 (1974).

METHODS Preparation of Leukocytes

Blood is drawn from allergic donors (chosen on the basis of adequatehistamine release induced by a challenge), using standard venipuncturemethods, into Vacutainers with EDTA in water as anticoagulant. The bloodsamples are placed briefly on a rotary mixer. The blood is mixed withHespan (hydroxy ethyl starch, 0.5 ml per 1.0 ml of blood), the tubeinverted several times to mix and then left undisturbed at roomtemperature until a sharp separation is observed between the settled redcells and the leukocyte and platelet-rich plasma. This usually occurswithin 35-45 minutes.

The plasma fraction is removed and centrifuged for 12 minutes at 4° C.at 1050 RPM (100 Xg). The platelets remain in the plasma and arediscarded. The pelleted leukocytes are shaken gently to disrupt the cellbutton and washed twice with HA buffer containing 0.005M EDTA andresuspended in HACM buffer to approximately one-quarter the originalblood volume. A sample is prepared for Hematology, where a total whiteblood cell and platelet count is done using a Coulter Counter.

Protocol Design

Aliquots (0.1 ml) of cells are added to triplicate assay tubescontaining 0.4 ml of either 6% perchloric acid (for total histaminecontent), vehicle control (for spontaneous release), or drug. The tubesare incubated at room temperature for 8 minutes, and then placed in a37° C. water bath for 2 more minutes. Buffer or challenge agents (at 37°C.) are added to the tubes and they are incubated for an additional 45minutes at 37° C. in a shaking water bath. The tubes are then spun at2000 RPM (1200 g) for 3 minutes to pellet the cells and the supernatantsare removed and assayed for histamine by the fluorometric method.

Drug Preparation

A 300 μM stock solution of each test compound is prepared in distilledwater, using 0.5 ml DMSO/100 ml and/or 0.2 ml of 1N NaOH or HCl and/orheat to aid in dissolution. Five ml of the stock solution is diluted(1:2) with 5 ml of two times concentrated HACM buffer to yield the stockworking concentration of 150 μM. When added to the cells and stimulus, afinal test concentration of 100 μM drug results. Further dilutions aremade with HACM buffer for 33, 10, 3.3, 1.0 μM, etc.

Challenge Agent Preparation

Short ragweed and house dust extracts (Greer Laboratories, Inc.) aresupplied as aqueous extracts in stock concentrations of 40,000 and10,000 protein nitrogen units per milliliter (PNU/ml), respectively.Aqueous solutions of anti-IgE antisera (rabbit-raised antibody) arepurchased from Dako via Accurate Chemicals. The aqueous solutions ofragweed, house dust, and anti-IgE are diluted 1:2 with two timesconcentrated HACM and then further diluted with HACM to yield finalstock concentrations of 6000 PNU/ml for ragweed and house dust and 1:50dilution for the anti-IgE antisera. Further dilutions for workingsolutions are made in HACM buffer. All stock and working solutions arestored at 4° C. Working solutions comprise 1/6 of the final volume inthe cell reaction, therefore, working solutions of challenge agents aremade up six times the required final concentration.

In each experiment, cells are challenged according to the previouslydetermined sensitivity of that donor to the particular challenge agent.Short ragweed and house dust concentrations are expressed in PNU/ml, andanti-IgE antisera is expressed as dilutions, e.g., IE-5 (1:100,000),3E-5 (1:30,000), and IE-4 (1:10,000).

Calculation and Interpretation of Results

The total histamine concentration in the "total" (acid-treated) samplesmust be 15 ng/ml to be acceptable. Spontaneous release of histamine fromthe cells should not exceed 15% of the total histamine, and isfrequently <5%. The maximum percentage histamine released varies withthe donor. The net amount released by the challenge agent must exceed25% of the total cellular histamine to confidently assess inhibition bytest compounds. Spontaneous histamine release is subtracted from both"totals" and challenged cells to calculate net percent release. Percentinhibition is shown in the Table and is calculated using the followingformula: ##EQU1##

                  TABLE                                                           ______________________________________                                                                              HHB                                                                           % Inhibition of                                                               Histamine Release                       Ex   R.sub.1                                                                              R.sub.2   R.sub.3                                                                             R.sub.4                                                                            R.sub.5                                                                            at 33 μM                             ______________________________________                                        1    MeO    MeO       H     H    H    *                                       2    MeO    H         OMe   H    H    *                                       3    MeO    H         H     OMe  H    86                                      4    MeO    OMe       OMe   H    H    *                                       5    MeO    H         OMe   OMe  H    73                                      6    H      OMe       OMe   OMe  H    92                                      7    Cl     H         Cl    H    H    81                                      8    H      Cl        Cl    H    H    88                                      9    H      OMe       OMe   H    H    84                                      10   H      OMe       OH    OMe  H    90                                      11   H      F         OMe   H    H    94                                      12   H      OH        OH    H    H    41                                      13   H      Br        OH    H    H    61                                      14   H      Br        OH    Br   H    *                                       15   H      Me        OH    Me   H    84                                      16   H      OMe       OH    Br   H    51                                      17   H      H         H     H    H    39                                      18   MeO    H         H     H    H    *                                       19   H      MeO       H     H    H    100                                     20   H      H         MeO   H    H    90                                      21   H      OH        H     H    H    75                                      22   H      H         OH    H    H    95                                      23   H      OEt       H     H    H    *                                       24   H      OCHMe.sub.2                                                                             H     H    H    *                                       25   H      OCH.sub.2 Ph                                                                            H     H    H    *                                       26   H      Me        H     H    H    58                                      27   H      CF.sub.3  H     H    H    58                                      28   H      Cl        H     H    H    *                                       29   H      Br        H     H    H    *                                       30   H      NO.sub.2  H     H    H    *                                       31   H      H         Cl    H    H    95                                      32   H      H         Br    H    H    61                                      33   H      H         OPh   H    H    64                                      34   H      H         NO.sub.2                                                                            H    H    *                                       35   H      H         SMe   H    H    *                                       36   H      MeO       OH    H    H    79                                      37   H      MeO       H     MeO  H    80                                      38   H      H         Me    H    H    30                                      39   H      H         Ph    H    H    28                                      40   Cl     Cl        H     H    H    60                                      41   Cl     H         H     H    Cl   *                                       43   H      F         H     H    H    *                                       44   OH     H         H     H    H    *                                       45   H      OH        OMe   H    H    59                                      47   H      OH        OMe   OMe  H    79                                      48   OMe    H         H     H    OMe  *                                       49   OH     H         H     OMe  H    98                                      50   H      OH        H     OMe  H    96                                      51   H      OMe       OH    tBu  H    34                                      52   OH     H         OMe   OMe  H    79                                      53   H      Me.sub.2 NCH.sub.2                                                                      OH    MeO  H    *                                       54                                    85                                      55                                    88                                      56                                    26                                      57                                    66                                      58                                    24                                      59                                    72                                      103                                   95                                      104                                   87                                      105                                   88                                      106                                   84                                       ##STR22##                                                                    63   H      MeO       OH    MeO  H    60                                      64   H      tBu       OH    tBu  H    49                                      65   H      H         H     H    H    *                                       66   H      OMe       H     H    H    92                                      67   H      H         OMe   H    H    90                                      68   H      OMe       OH    H    H    81                                       ##STR23##                                                                    69   H      MeO       OH    H    H    77                                      70   H      MeO       H     H    H    58                                      71   H      H         MeO   H    H    83                                      72   H      MeO       MeO   H    H    43                                      73   H      MeO       OH    Meo  H    89                                      74   H      Me        OH    Me   H    88                                      75   H      Br        OH    MeO  H    *                                       76   MeO    H         MeO   MeO  H    *                                       77   H      MeO       MeO   MeO  H    76                                      107  H      Br        OH    H    H    66                                       ##STR24##                                                                    80   H      Br        OH    Br   H    85                                      82   H      Br        OH    H    H    78                                      83   H      tBu       OH    tBu  H    30                                      84   OMe    H         H     H    H    *                                       85   H      OMe       H     H    H    28                                      86   H      H         OMe   H    H    *                                       87   H      OMe       OH    H    H    *                                       88   H      OMe       OH    OMe  H    68                                       ##STR25##                                                                    89   H      MeO       AcO   H    H    27                                      90   H      MeO       OH    H    H    *                                       91   H      MeO       OH    MeO  H    *                                       92   H      tBu       OH    tBu  H    11                                       ##STR26##                                                                    93   MeO    H         H     H    H    *                                       94   H      MeO       H     H    H    *                                       95   H      H         MeO   H    H    *                                       96   H      MeO       OH    H    H    58                                      97   H      MeO       OH    MeO  H    51                                       ##STR27##                                                                    98   H      MeO       H     H    H    *                                       99   H      MeO       OH    H    H    92                                      100  H      MeO       OH    MeO  H    68                                      101  H      Br        OH    Br   H    96                                      ______________________________________                                         *Indicates not active at 33 μM.                                            E Enhanced release at this concentration.                                     MeO is methoxy.                                                               OCHMe.sub.2 is isopropoxy.                                                    OCH.sub.2 Ph is benzyloxy.                                                    tBu is tertiarybutyl.                                                         Me.sub.2 NCH.sub.2 is dimethylamine.                                     

Activity is measured as % inhibition of histamine release from humanbasophils challenged with anti-IgE at a 33 μM concentration of drug.

The IC₅₀ is calculated to give the μM necessary to provide 50%inhibition.

The usefulness of the compounds of the present invention as inhibitorsof the 5-lipoxygenase enzyme, cyclooxygenase, or in treating relateddiseases or conditions may be demonstrated by their effectiveness invarious standard test procedures. A description of each procedurefollows.

ARBL/ARBC Whole Cell 5-Lipoxygenase and Cyclooxygenase Assays Materials

The rat basophilic leukemia cell line (RBL-1) was obtained from theAmerican Type Culture Collection (Rockville, Md.).

Radioimmunoassay (RIA) kits of LTB₄ and PGF₂.sbsb.α were obtained fromAmersham (Arlington Heights, Ill.) and Seragen (Boston, Mass.),respectively.

All tissue culture media were obtained from GIBCO (Grand Island, N.Y.).

Method

RBL-1 cells are grown in suspension culture in Eagle's minimum essentialmedium supplemented with 12% fetal bovine serum at 37° C. in anincubator supplied with air-5% carbon dioxide. Cells are harvested bycentrifugation. They are washed with cold phosphate buffered saline pH7.4 (PBS; NaCl, 7.1 g; Na₂ HPO₄, 1.15 g; KH₂ PO₄, 0.2 g; and KCl, 0.2g/l). Cells are finally suspended in PBS containing 1.0 mM calcium at adensity of 2×10⁶ cells/ml. Cells are incubated with and without testagent (in DMSO) (1% DMSO is without effect on arachidonic acidmetabolism) for ten minutes at room temperature. Calcium ionophoreA23187 (5 μM) is added and cells are incubated for seven minutes at 37°C. The reaction is stopped by chilling the tubes on ice for ten minutes.Cells are separated by centrifugation and the supernatant is stored at-20° . Aliquots (100 μl) are analyzed for LTB₄ and PGF₂.sbsb.α usingradioimmunoassay kits as provided by the supplier.

Table 1 contains biochemical data obtained from this whole cell assay asICsos which are calculated as the amount of test compound causing 50%inhibition of LTB₄ or PGF₂.sbsb.α formation.

Carrageenan-Induced Rat Foot Paw Edema-2 (CEF-2) Assay: Protocol

Carrageenan solution (1% w/v) is prepared by dissolving 100 mgcarrageenan (Marine Colloidal Div., Springfield, N.J.) in 10 ml ofsterile saline (0.9%) solution (Travenol). The solution is vortexed for30 to 45 minutes. Animals are dosed with compound one hour beforecarrageenan challenge. Foot paw edema is induced by injecting 0.10 ml ofthe 1% carrageenan subcutaneously into the plantar portion of the righthind paw of each rat under light anesthesia. Initial foot paw volume ismeasured immediately following carrageenan challenge using mercuryplethysmography (Buxco Electronics). Edemia is measured five hours aftercarrageenan. The difference between the five-hour and the initial pawvolume is expressed as delta edema. The delta edema for each test groupof animals is used to calculate the percent inhibition of edema achievedby the compound at the test dose compared with the vehicle controlgroup. The ID₄₀ (the dose at which swelling is inhibited by 40%) iscalculated by probit analysis for the dose at which 40 percentinhibition occurs.

                  TABLE II                                                        ______________________________________                                        Example No.                                                                              ARBL.sup.(1) ARBC.sup.(2)                                                                           CFE.sup.(3)                                  ______________________________________                                         64        100          95       31.8 (1)                                                                      39.8 (3)                                                                      53.7 (10)                                                                     58.8 (30)                                    108        92           86       44.1 (1)                                                                      41.1 (3)                                                                      32.1 (10)                                                                     40.4 (30)                                    109        95           89       18.5 (1)                                                                      23.5 (3)                                                                      36.8 (10)                                                                     39.4 (30)                                    110        67           N.sup.(4)                                              32        93           59                                                    ______________________________________                                         .sup.(1) Percent inhibition of cellular 5lipoxygenase at 16 μM.            .sup.(2) Percent inhibition of cellular 5 cyclooxygenase at 16 μM.         .sup.(3) Percent inhibition of carrageenan footpad edema (CFE) test at        various doses (mg/kg) of test drug.                                           .sup.(4) N inactive at screening concentration.                          

Accordingly, the present invention also includes a pharmaceuticalcomposition for treating one of the above diseases or conditionscomprising an antidisease or anticondition effective amount of acompound of the formula I as defined above together with apharmaceutically acceptable carrier.

The present invention further includes a method for treating one of theabove named diseases or conditions in mammals, including man, sufferingtherefrom comprising administering to such mammals either orally orparenterally, preferably oral, a corresponding pharmaceuticalcomposition containing a compound of formula I as defined above inappropriate unit dosage form.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granues, capsules, cachets, and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet disintegrating agents; it can also be encapsulatingmaterial. In powders, the carrier is a finely divided active compound.In the tablet the active compound is mixed with carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5 or 10 to about 70 percent of the active ingredient. Suitablesolid carriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, a low melting wax, cocoa butter, and thelike. The term "preparation" is intended to include the formulation ofthe active compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by dissolving the active componentin water and adding suitable colorants, flavors, stabilizing andthickening agents as desired. Aqueous suspensions suitable for oral usecan be made by dispersing the finely divided active component in waterwith viscous material, i.e., natural or synthetic gums, resins,methylcellulose, sodium carboxymethylcellulose, and other well-knownsuspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions, and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit. Alternately, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon, or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e., under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents, and the like. The liquid utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerine, propylene glycol, and the like as well as mixturesthereof. Naturally, the liquid utilized will be chosen with regard tothe route of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 500 mg preferably to 1 to 50 mgaccording to the particular application and the potency of the activeingredient. The compositions can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as described above, the dosages may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with the smaller dosageswhich are less than the optimum dose of the compound. Thereafter thedosage is increased by small increments until the optimum effect underthe circumstances is reached. For convenience, the total daily dosagemay be divided and administered in portions during the day if desired.

In addition to the compounds of formula I, the pharmaceuticalcompositions can also contain other active ingredients, such ascyclooxygenase inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs),peripheral analgesic agents such as zomepirac, diflunisal, and the like.The weight ratio of the compound of the formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the formula I is combined with an NSAID, theweight ratio of the compound of the formula I to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the formula I andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Combinations of a compound of the formula I and other active ingredientswill generally be in the aforementioned ratios.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: ibuprofen,ibuprufen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen,flurbiprofen, fenoprofen, fenbufen, pirprofen, carprofen, oxaprozin,pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen,fluprofen, and bucloxic acid. Structurally related propionic acidderivatives having similar analgesic and antiinflammatory properties arealso intended to be included in this group.

Thus, "propionic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻Na⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozicacid. Structurally related acetic acid derivatives having similaranalgesic and antiinflammatory properties are also intended to beencompassed by this group.

Thus, "fenamic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs which contain the basicstructure: ##STR28## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and antiinflammatory properties arealso intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenonnarcotic analgesics/nonsteroidal antiinflammatory drugs which containthe basic structure: ##STR29## which can bear a variety of substituentsand in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO⁻ Na⁺.

The oxicams which can be used in the present invention comprise:piroxicam, sudoxicam, isoxicam, and 4-hydroxyl-1,2-benzothiazine1,1-dioxide 4-(N-phenyl)-carboxamide. Structurally related oxicamshaving similar analgesic and antiinflammatory properties are alsointended to be encompassed by this group.

Thus, "oxicams" as defined herein are nonnarcoticanalgesica/nonsteroidal antiinflammatory drugs which have the generalformula: ##STR30## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: acemetacin, alminoprofen, amfenacsodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazaclysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen,cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet,delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine,difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole,etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac,fenclorac, fendosal, fenflumizole, fentiazac, feprazone, floctafenine,flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal,furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac,isonixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide,lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin,clonixinate, meclofenamate sodium, meseclazone, microprofen, nabumetone,nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin,perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, pirprofen, pranoprofen, proglumetacin maleate, proquazone,pyridoxiprofen, sudoxicam, suprofen, talmetacin, talniflumate,tenoxicam, thiazolinobutazone, thielavin B, tiaprofenic acidd, tiaramideHCl, tiflamizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol,tryptamid, ufenamate, and zidometacin.

Finally, NSAIDs which may also be used include the salicylates,specifically aspirin, and the phenylbutazones, and pharmaceuticallyacceptable salts thereof.

Pharmaceutical compositions comprising the formula I compounds may alsocontain as the second active ingredient, antihistaminic agents such asbenadryl, dramamine, histadyl, phenergan, and the like. Alternatively,they may include prostaglandin antagonists such as those disclosed inEuropean Patent Application 11,067 or thromboxane antagonists such asthose disclose din U.S. Pat. No. 4,237,160. They may also containhistidine decarboxylase inhibitors such as α-fluoromethylhistidine,described in U.S. Pat. No. 4,325,961. The compounds of formula I mayalso be advantageously combined with an H₁ or H₂ -receptor antagonist,such as for instance cimetidine, ranitidine, terfenadine, famotidine,temelastine, acrivastine, loratidine, cetrizine, tazifylline,azelastine, aminothiadiazoles disclosed in EP 81102976.8 and likecompounds, such as those disclosed in U.S. Pat. Nos. 4,283,408;4,362,736; 4,394,508, and European Patent Application No. 40,696. Thepharmaceutical compositions may also contain a K⁺ /H⁺ ATPase inhibitorsuch as omeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Each of the references referred to in this paragraph is herebyincorporated herein by reference.

Thus, "acetic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free --CH₂ COOHgroup (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g., --CH₂ COO⁻ Na⁺), typically attacheddirectly to a ring system, preferably to an aromatic or heteroaromaticring system.

We claim: 1.5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)]-methylene]-2,4-thiazolidinedioneor a pharmaceutically acid addition salt thereof.
 2. The choline salt ofthe compound of claim
 1. 3. A pharmaceutical composition comprising acompound of claim 1 or a pharmaceutical acceptable salt thereof togetherwith a pharmaceutical acceptable carrier.
 4. A pharmaceuticalcomposition as claimed in claim 3 additionally comprising an effectiveamount of a second active ingredient that is a nonsteroidalantiinflammatory drug; a peripheral analgesic agent; a cyclooxygenaseinhibitor; a leukotriene antagonist; an antihistaminic agent; aprostaglandin antagonist or a thromboxane antagonist.
 5. A compositionof claim 3 wherein the compound is5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2,4-thiazolidinedione.6. A method for treating allergies in a human suffering therefrom whichcomprises administering an antiallergy effective amount of thecomposition of claim 3 in unit dosage form.
 7. A method for use as anantiinflammatory agent comprising an antiinflammatory amount of thecomposition for claim 3 in unit dosage form.